Review
Bladder cancer, a two phased disease?

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Abstract

The processes of intraepithelial migration, intraluminal seeding, and field cancerization as models for initiation, spread, and recurrences of urothelial cell carcinoma (UCC) are reviewed in light of recent molecular investigations. The accumulated molecular data on synchronous and metachronous tumors indicate that the majority of recurrent and multiple tumors are monoclonal. Molecular data has also shown the presence of chromosomal and genetic changes in precursor lesions as well as in normal urothelial cells. Genetic-histological mapping of cystectomized bladders has shown that overt tumors occur as local events in areas of genetically altered urothelium. A model is put forward in which the tumor process is initiated by genetically altered but histologically normal cells that produce fields of altered cells by intraepithelial displacement. By the accumulation of further genetic changes the fields of altered urothelium reaches a state of criticality, which locally may produce frank tumors.

Section snippets

Urothelial cell carcinoma

Urothelial cell carcinomas (UCC) originate from the epithelial cells of the inner lining of the bladder wall. Seventy percent of the tumors are papillary and confined to the urothelial mucosa (stage Ta) or to the lamina propria (stage T1), whereas the remaining invade the muscle (T2), perivesical fat (T3) or surrounding organs (T4) (Fig. 1). It is not uncommon for patients with Ta/T1 tumors to show multiple, synchronous tumors. Most Ta tumors are of low grade (G1 or G2), rarely progress, and

Intraepithelial migration, intraluminal seeding, and field cancerization

Two major hypotheses have been proposed to explain the origin of synchronous and metachronous tumors in patients with UCC (Fig. 2). One assumes a monoclonal origin either through intraepithelial migration of tumor cells or by intraluminal seeding from a primary carcinoma. The second, the field cancerization model, proposes a field change and that individual cells in these fields are transformed to overt tumors and states, in the stronger version, that independent genetic events will produce

Premalignant lesions and normal urothelium show genetic changes found in cancer cells

There is growing evidence for the presence of chromosomal and genetic changes characteristic of UCC already in premalignant lesions. Hartmann et al. [6] showed that 10 out of 14 hyperplasias showed monosomies or partial loss of chromosome 9. In seven out of eight patients with genetic alterations in the hyperplasias the genetic changes were also present in the concomitant papillary tumors. In two out of six investigated patients chromosome 9 deletions were also detected in biopsies of normal

Recurrences, multifocal tumors, and the question of clonality

To investigate the possible multiclonality among multiple tumors from the same patient Sidransky et al. [19] analyzed 13 tumors from four different patients by chromosome X-inactivation analysis. In each case the tumors showed X-inactivating patterns consistent with a monoclonal origin. Li et al. [20] studied 10 patients with both synchronous and metachronous Ta/T1 tumors by X-chromosome inactivation analyses. Tumors from the same patient showed the same X-inactivation pattern indicating a

Histologic-genetic mapping

Using X chromosome inactivation analysis of cells microdissected from histological slides from a normal female human bladder, Tsai et al. [27] showed that the normal urothelium was organized in patches of monoclonal segments. These patches were about 120 mm2 and estimated to contain approximately 2 × 106 cells. Tsai et al. suggested that the patches were composed of descendants of an original founder cell, a stem cell, and estimated the number of such cells to 200–300 per bladder. This suggests

The chronology of tumor presentation does not parallel the genetic evolution

van Tilborg et al. [31] studied 11 patients with five or more recurrences using LOH and mutation analyses. For each patient tumor progression trees were constructed based on the accumulating number and sizes of the genetic changes, creating a chronology of the recurrences based on genetic events. By comparing the genetic chronology with the chronology of tumor appearance it was found that the genetic progression trees better reflected the tumor evolution than their chronologic order of

Two phases of bladder cancer

The data favoring the presence of genetic changes characteristic of frank carcinomas in morphologically normal urothelium, including LOH, chromosomal changes, and gene mutations, is more than convincing. The use of microdissection has successfully showed that premalignant lesions, hyperplasias, papillary hyperplasias, and dysplasias, adjacent to tumors show genetic aberrations similar to those in overt tumors. The detailed histologic-genetic mapping shows that regions with shared genetic

Consequences for treatment

The concept of expanded fields of preneoplastic cells that may function as a potent source for initiation of new tumor foci has important clinical consequences. One of the key challenges in the management of UCC is the high frequency of recurrences. Some success in prolonging the recurrence-free period after transurethral resection (TUR) have been accomplished by combining TUR with intravesical chemo- or immunotherapy. It is conceivable that the selective action of many chemotherapeutic agents

Acknowledgements

This work was supported by Swedish Cancer Society, the Swedish Research Council, the Petrus and Augusta Hedlunds foundation, Gunnar, Arvid and Elisabeth Nilsson foundation, and the Crafoord foundation. The author thanks Dr. Wiking Månsson at the Department of Urology, Lund University Hospital, for critically reading the manuscript.

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